JP2008533037A - Benzoyl peroxide composition and method of use - Google Patents

Abstract

Compositions for the treatment of acne infections that are more effective than conventional compositions; compositions in which benzoyl peroxide is in solution and / or in low concentrations; and, for example, benzoyl peroxide by dissolving the material in a suitable solvent Providing ways to improve processing.
A composition comprising a solution of benzoyl peroxide in one or more solvents and further comprising an additional active ingredient effective to treat acne. A benzoyl peroxide / solvent solution is prepared by combining benzoyl peroxide and at least one solvent, and the benzoyl peroxide / solvent solution is applied topically to the skin, in which case percutaneous absorption of benzoyl peroxide is achieved. A method for improving the transdermal absorption of a benzoyl peroxide composition applied topically to a user's skin consisting of increasing compared to the application of an undissolved benzoyl peroxide composition.
[Selection] Figure 2

Description

  The present invention relates to the manufacture of a composition comprising benzoyl peroxide in a solution for topical application to human skin. These compositions are useful for the treatment and prevention of acne with greater efficacy than conventional compositions. This composition allows the benzoyl peroxide to be utilized in the form of new products and has a unique processing capability that makes them useful in areas other than acne treatment. Moreover, this composition increases the percutaneous absorption of benzoyl peroxide in the skin.

  Benzoyl peroxide is a crystalline solid having a melting point of 103-106 ° C. and a molecular weight of 242.22. Purified benzoyl peroxide is highly flammable and sensitive to impact, and is therefore mostly used in a water-containing form, usually containing 25% water and 75% benzoyl peroxide crystals. This material is like sand and is very hard and difficult to process and grind to be formulated into product forms such as dispersions. The use of dispersions limits clear product and spray formulations. Benzoyl peroxide is toxic and has some solubility in certain industrial solvents such as benzene and toluene aromatic solvents that are not suitable for human use. Ketone-based solvents such as methyl ethyl ketone and acetone are also known, but the ability of these solvents, such as their flammability and irritation and peeling their skin from their protective skin, is useful for drugs or cosmetics. Limit the use of the composition. U.S. Patent No. 6,057,031 discloses that long chain alkyl benzoates can be used to produce dispersions of crystalline benzoyl peroxide without the conventionally required grinding method. Second, it teaches that this combination removes water from the crystals and produces an almost anhydrous dispersion of benzoyl peroxide in the long chain alkyl benzoate ester. However, it does not teach that there is functionality in the solubility of these esters, and only describes products with benzoyl peroxide as a dispersion.

  Currently, a dispersion of benzoyl peroxide particles is used for the treatment of Acne vulgaris. Acne vulgaris appears to be caused by a number of factors, resulting in the formation of closed chalazion and acne with open comedones. These are solid, hard things that plug the follicles and appear to be caused by the production of excess vesicular sebum usually caused by hormonal changes. The composition of these hard masses is a tightly packed keratinized group of cells mixed with sebum, bacteria and other skin substances. As the comedones expand due to the accumulation of keratinized cells, sebum, bacteria, etc., pressure builds up in the follicular walls until the follicles rupture and dislodge these contaminants in the surrounding skin. The skin responds by an inflammatory reaction that takes the form of a pustules (pimples) for small ruptures or sac nodules for complete ruptures.

A recent method of treating Acne vulgaris is to treat the skin with a benzoyl peroxide dispersion of crystals. P. pylori, a microorganism that has been identified as a major infection of pustules using benzoyl peroxide. Used to control Acne bacilli. However, the use of essentially undissolved benzoyl peroxide crystals that are larger than the microorganism being treated is very ineffective and requires a high percentage of active to obtain effectiveness. In addition, crystals are extremely difficult to penetrate into because the blockage is a physical barrier and the size of the follicular opening is limited.
US Pat. No. 5,632,996

  Therefore, what is needed is a composition for the treatment of acne infections that is more effective than conventional compositions; a composition in which benzoyl peroxide is in solution and / or low concentration; and, for example, dissolving the material in a suitable solvent To improve the treatment of benzoyl peroxide. It would be advantageous to provide processing benefits for areas other than use in the pharmaceutical and cosmetic fields.

  Described herein are benzoyl peroxide compositions comprising a solution of benzoyl peroxide in one or more solvents. In particularly useful embodiments, the solution of the present invention comprises benzoyl peroxide and optional additional active or inactive ingredients, and a solvent or mixture of solvents in which benzoyl peroxide is produced as a clear solution. The solution is suitable for direct topical application to the user's skin and / or delivery of benzoyl peroxide into the comedones. In some embodiments, the antimicrobial agent is in the form of a solution so that when applied to the skin, the dissolved antimicrobial agent is in intimate contact with the cell walls of the microorganism. Dissolved benzoyl peroxide essences and formulations containing them should be effective in treating Acne vulgaris because the antimicrobial effectiveness is maximized when the microbe is attacked by the antimicrobial agent at the molecular level Has been found.

  In one aspect, a preferred therapeutic composition according to the present invention provides a solvent vehicle formulation for the treatment of acne where the main active ingredient is benzoyl peroxide. Benzoyl peroxide is provided in clear product forms such as serums, toners, pumps or aerosol sprays, clear gels, sticks, creams, lotions and mousses. Transparent product forms can be incorporated into other pharmaceutical or cosmetic product forms such as emulsions.

  Furthermore, the dermatological treatment formulation according to the invention can improve the skin characteristics of the user. The formulation includes the application of one or more therapeutic benzoyl peroxide compositions according to the present invention suitable for treating one or more skin conditions. Suitable therapeutic compositions include, for example, benzoyl peroxide serums and formulations for treating Acne vulgaris.

In a related aspect, the present invention relates to the treatment of skin lesions by application to the skin of one or more therapeutic compositions such as one or more benzoyl peroxide serums.
In another related aspect, the invention relates to increased transdermal absorption of topically applied benzoyl peroxide.
These and other aspects of the invention will become apparent in connection with the following detailed description.

  The present invention provides compositions and methods for treating acne. The system includes applying a predetermined amount of active pharmaceutical benzoyl peroxide in the form of a solution to the area of the skin in need thereof. Solvated benzoyl peroxide molecules can be utilized to penetrate into the follicles of the skin in need of treatment, including infected areas, the follicular sebaceous glands, the stratum corneum and the epidermis. Benzoyl peroxide saturates in the targeted infected area and P.I. Kill Acne bacteria. Since the infiltrated benzoyl peroxide is in the form of a solution, it is used in the skin that needs it in the most effective form.

  Thus, the compositions of the present invention provide a solvent vehicle formulation for the treatment of acne where the main active ingredient is benzoyl peroxide. In some embodiments, the active ingredients are provided in the form of transparent products that are not conventionally obtainable. Such transparent product forms include serums, toners, pumps or aerosol sprays, transparent gels, sticks, creams, lotions and mousses. The clear product form improves the effectiveness of the applied ingredients, allows for lower levels of use and results in faster patient response. Also, the use of these media solvents in the form of emulsion products allows benzoyl peroxide levels in oil / water emulsions that exceed the solubility parameter of benzoyl peroxide in oil / water systems without solvent media, This results in a slurry-type application with increased antimicrobial activity due to the dissolved fraction of benzoyl peroxide. In addition, the use of solvents with relatively low water solubility and relatively high solubility in benzoyl peroxide is more effective than long chain alkyl benzoates to remove water from crystals during processing and is safer for other industrial uses. Provide a way to handle.

  In one embodiment, the composition according to the invention comprises benzoyl peroxide in the form of a solution in one or more solvents. Benzoyl peroxide is usually commercially available either in purified (98% active) crystals or in a wet crystalline state containing 70-80% active benzoyl peroxide in 20-30% water. All commercially available forms of benzoyl peroxide are mixed with the disclosed solvents to form the composition according to the invention.

  The amount of benzoyl peroxide mixed with the solvent will vary depending on a number of factors including, for example, the activity of the benzoyl peroxide, the final form of the product, and the particular disclosed solvent used. Generally, benzoyl peroxide represents 1-70% by weight of the benzoyl peroxide / solvent mixture. In some embodiments, the benzoyl peroxide comprises about 3.00 to about 40% by weight of the benzoyl peroxide / solvent mixture. In some embodiments, the benzoyl peroxide comprises about 2 to about 15 weight percent of the benzoyl peroxide / solvent mixture. In some embodiments, benzoyl peroxide is present in an amount effective to treat Acne vulgaris. Due to the increased availability of benzoyl peroxide in the compositions of the present invention (shown in the examples below), the lowest effective amount of benzoyl peroxide is currently available including benzoyl peroxide in some embodiments. Will be lower than the amount in acne treatment. Thus, the composition according to the present invention comprises 5% benzoyl peroxide and has 2-3 times the skin penetration than conventional 10% benzoyl peroxide compositions.

  Solvents useful for making the solutions of the present invention include all solvents that can solubilize benzoyl peroxide. Examples of these solvents include, but are not limited to, short chain alkyl esters of benzoic acid, ethers, aldehydes or alcohols, benzyl alcohol, salicylic acid or phthalic acid. Other suitable solvents include aryl esters of benzoic acid, ethers, aldehydes, ketones and alcohols, benzyl alcohol, salicylic acid, phenol and phthalic acid. In one embodiment, the composition according to the invention comprises one or more of the following groups of solvents: Alkyl ester of benzoic acid, alkyl ester of benzyl alcohol, alkyl ester of salicylic acid, alkyl ester of phenol, alkyl ester of phthalic acid, alkyl ether of benzyl alcohol, alkyl ester of phthalic acid, alkyl ether of benzyl alcohol, phenol alkyl ether. Additional examples of suitable solvents include benzoyl benzoate, benzoyl alcohol, diethyl phthalate, 2-phenylethyl ester benzoate, methyl salicylate, ethyl salicylate, propyl salicylate, butyl salicylate, ethyl benzoate, benzoic acid Methyl, propyl benzoate, butyl benzoate, dimethyl phthalate, diethyl phthalate, benzyl ethyl ether, benzyl methyl ether, phenetol, phenyl acetone, phenyl ethyl alcohol, phenoxy ethanol, phenyl acetaldehyde, ethyl phenyl acetate, phenyl methyl ketone, phenyl acetate Benzyl acetate, benzyl acetoacetate, benzyl formate, benzaldehyde, benzyl alcohol, ethyl benzyl alcohol, salicylaldehyde, benzylsartile DOO, phenyl tolyl ketone, phenyl benzoate, phenyl ether, dibenzyl ether, benzyl benzoate, including benzoic acid and 2-phenylethyl ester 2, and the like.

  The amount of solvent mixed with benzoyl peroxide will vary depending on a number of factors including, for example, the final form of the product and the particular solvent used. Generally, the solvent will comprise 1-70% by weight of the benzoyl peroxide / solvent mixture. In some embodiments, the solvent comprises about 10 to about 50% by weight of the total composition. In some embodiments, the solvent comprises about 20 to about 40% by weight of the total composition. In some embodiments, the solvent is present in an amount effective to dissolve benzoyl peroxide.

In addition to the solvent in which benzoyl peroxide is soluble, the composition according to the invention can comprise one or more secondary solvents. Suitable secondary solvents include, for example, ethanol, acetone, dimethyl isosorbide, and glycol ethers of C ₁ -C ₆ alcohols using up to 2 moles of ethylene oxide. Preferred glycol ethers are glycol glycol ethers of phenol using up to 2 moles of ethylene oxide, glycol ethers of methanol using up to 2 moles of ethylene oxide, glycol ethers of ethanol using up to 2 moles of ethylene oxide, and up to 2 moles of ethylene oxide. Contains glycol ether of propanol using Examples of these cosolvents include, but are not limited to, phenoxyethanol, ethoxydiglycol and propylglycol methyl ether.

  The amount of secondary solvent mixed with the benzoyl peroxide / solvent mixture will vary depending on a number of factors including, for example, the final form of the product and the particular solvent / secondary solvent used. In general, the secondary solvent will comprise 1-40% by weight of the total composition. In some embodiments, the secondary solvent will comprise from about 5 to about 30% by weight of the total composition. In some embodiments, the secondary solvent will comprise from about 10 to about 20% by weight of the total composition.

  To prepare some compositions according to the present invention, benzoyl peroxide is simply mixed with the disclosed solvent, which occurs at room temperature. As already mentioned, benzoyl peroxide is usually marketed either as purified crystals or in a wet crystalline state. Any of these or other forms of benzoyl peroxide are mixed with the disclosed solvent to form a composition according to the present invention.

  In addition to benzoyl peroxide, the compositions of the present invention also optionally include salicylic acid, antibiotics and / or any other material in an amount effective for acne treatment. Antimicrobial agents that can be combined with the benzoyl peroxide compositions according to the present invention include all antibiotics, antimicrobial agents and antimicrobial peptides. Examples of suitable antibiotics are in particular the dermatologically acceptable salts of tetracycline and tetracycline derivatives, gentamicin, kanamycin, streptomycin, neomycin, capreomycin, lineomycin, paramomycin, tobramycin, erythromycin, triclosan, octopirox, para Chlorometaxylenol nystatin, tolnaftate, miconazole hydrochloride, chlorhexidine gluconate, chlorhexidine hydrochloride, methanamine hippurate, methanamine mandelate, minocycline hydrochloride, clindamycin, cleosin, b-lactam derivatives such as aminopenicillin and these Including but not limited to mixtures. In some embodiments, a combination of chlorhexidine gluconate and triclosan is suitable for use in the present invention. In certain embodiments, antimicrobial agents that can be used according to the present invention, either alone or in combination, include, for example, benzoyl peroxide and salicylic acid.

  The amount of antibiotic mixed with the benzoyl peroxide / solvent mixture will vary depending on a number of factors including, for example, the final form of the product and the particular solvent and / or secondary solvent used. In general, the antimicrobial agent will comprise 1.0-30% by weight of the total composition. In some embodiments, the antibiotic comprises about 0.1 to about 5% by weight of the total composition.

  In some embodiments, benzoyl peroxide is added to a solvent to form a mixture at room temperature, eg, a temperature of 25 to about 27 ° C. In addition, the benzoyl peroxide / solvent mixture can also be added to other ingredients to form the desired product, such as an emulsion, lotion, cream or gel, at low temperatures. In these methods, the possibility of decomposition or combustion is greatly reduced because benzoyl peroxide is never in contact with substantial heat. However, an important difference between the disclosed prior art and the composition of the present invention is that benzoyl peroxide becomes an active solution at a high level, such as 10% by weight of the total formulation. . These solutions can provide new transparent products with increased effectiveness.

  Moreover, the higher affinity of benzoyl peroxide for the disclosed solvents provides an improved method of producing anhydrous benzoyl peroxide without exposing the composition to any heat during processing. For example, a benzoyl peroxide moist crystal containing 25% water is mixed with a solvent according to the present invention, the solvent (solubilizing benzoyl peroxide) is used to convert water during the process of converting crystalline benzoyl peroxide into a solution. Substituting and water can be easily separated. Second, if a level of benzoyl peroxide exceeding the solvent solubility parameter is desired, a saturated solution associated with a fine soft benzoyl peroxide slurry is formed. This composition is then filtered to remove water from the composition, thereby obtaining a fine textured, substantially moisture-reduced benzoyl peroxide paste / saturated solution composition. The benzoyl peroxide solution provides a method for using benzoyl peroxide in other industrial applications where an anhydrous solution offers advantages over dispersions. Furthermore, the present invention provides the advantage of more effective water removal if desired for the desired application.

  In some embodiments, thickeners and / or rheology modifiers such as fumigated silica can be added to the solution to increase the viscosity of the composition and / or gel. In some embodiments, the thickener and / or rheology modifier comprises about 0.1 to about 10% by weight of the total composition.

  As mentioned above, the benzoyl peroxide composition according to the present invention can be added to the product form. Suitable product forms include solutions, emulsions (including microemulsions), suspensions, creams, lotions, gels, sticks, powders or other typical solid or liquid compositions used for skin treatment. Including. These compositions are antibacterial agents, fresheners, solvent ingredients and other ingredients typically used in these products such as moisturizers and wettable powders, penetrants, preservatives, emulsifiers, natural or synthetic oils, surface active Contains detergents, detergents, gelling agents, emollients, antioxidants, fragrances, fillers, thickeners, waxes, odor absorbers, dyes, coolants, powders, viscosity control agents and water, and optionally, anti-irritant Contains active agents, plant extracts, conditioning agents, darkening or lightening agents, glitters, wetting agents, mica, minerals, polyphenols, silicones or derivatives thereof, sun block agents, vitamins and botanical agents. In some embodiments, the product form has an antioxidant to promote the stability of the formulation. Examples of suitable antioxidant compositions for use in accordance with the present invention are further described in, but not limited to, US patent application 60 / 660,387. The entirety of which is incorporated herein by reference.

  In one aspect, the composition according to the invention is useful for forming an oil-in-water emulsion product form. Conventional emulsion formulations typically mix (optionally in several stages) the aqueous phase component and the dispersant until a uniform solution or dispersion is obtained, and then a uniform solution or dispersion. Mix the organic phase ingredients with heating until the product is obtained (and optionally in several stages), then add the aqueous phase to the organic phase while stirring (eg stirring or other shearing or heating means) ) To form a two-phase oil-in-water emulsion. However, the heating step is problematic in that heat decomposes peroxides such as benzoyl peroxide. In some embodiments, emulsion compositions according to the present invention are capable of low temperature mixing and shearing that do not require a strong heating step above 70 ° C. Therefore, such mixing can be performed at room temperature.

  In some emulsion embodiments, the aqueous phase comprising the dispersion medium is any suitable surfactant, wetting agent, suspending agent, and / or buffer system suitable for mixing with benzoyl peroxide and / or combinations thereof. Can be included.

  Examples of suitable surfactants are natural compounds such as phospholipids and cholates or non-natural compounds such as polysorbates (which are fatty acid esters of polyethoxylated sorbitol), fatty acids from sugar such as polyethylene glycol esters of castor oil, polyethoxylated fatty acids such as Stearic acid, octylphenol poly (ethylene glycol ether), polyethoxylated isooctylphenol / formaldehyde polymer, poloxamer such as poly (oxyethylene) poly (oxypropylene) block copolymer, polyoxyethylene aliphatic alcohol ether, polyoxyethylene nonylphenyl ether, Including but not limited to polyoxyethylene isooctyl phenyl ether and SDS.

  In certain embodiments, examples of suitable mixtures of surfactants include, but are not limited to, mixtures of surfactants of different chemical types. Surfactants are suitable for cosmetic or pharmaceutical administration and are compatible with benzoyl peroxide to be delivered. Other examples of surfactants include, but are not limited to, phospholipids such as phosphatidylcholine (lecithin) (including soy or chicken egg lecithin). Other suitable phospholipids include phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, cardiolipin, and phosphatidylethanolamine. Phospholipids can be isolated from natural sources or produced synthetically.

Although the example of the suitable precipitation inhibitor manufactured from the following components is shown, it is not limited to these. Polyacrylamide, C _13-14 isoparaffin and laureth 7; C _13-14 isoparaffin, mineral oil, polyacrylate, polyacrylamide and ethoxylated sorbitan ester; acrylamide / sodium acryloyl dimethyl taurate copolymer, isohexadecane and ethoxylated sorbitan ester and their combination. However, any suitable cosmetic or pharmaceutically acceptable suspending agent suitable in combination with an organic peroxide can be used.

  An example of a suitable humectant is glycerin, but is not limited thereto. However, any material capable of obtaining moisture can be added if it is stable with benzoyl peroxide.

  Products formulated with the solutions of the present invention can be packaged in any type of container within the purview of those skilled in the art, including bottles, tubes, pump types, roll-on, brushes, wet tissue, etc. It is not limited.

  The benzoyl peroxide composition according to the present invention is applied topically to the skin in need of improvement in order to alleviate or eliminate undesirable skin symptoms. As used herein, the term “treat” or “treatment” prophylactically or to relieve existing unwanted skin symptoms such as Acne vulgaris to prevent the occurrence of undesirable skin symptoms. Therefore, it means to use the composition of the present invention therapeutically. A number of different treatments are currently possible and they alleviate and / or eliminate skin conditions such as Acne vulgaris.

  As used herein, “skin symptoms” refers to all detectable skin manifestations caused by one or more pathogens or microorganisms. These expressions are combined by a number of factors such as age aging, environmental damage and / or other disease or dysfunctional conditions. Examples of these manifestations include, but are not limited to, the development of skin wrinkles, indentations, streaks, comedones, depressions, scales, flaking and / or other forms of skin irregularities, rough or speckled appearances. It should be understood that the skin conditions shown are not limited thereto, and that only some of the skin conditions suitable for treatment according to the present invention are described herein.

  In some embodiments, the composition used in accordance with the present invention comprises benzoyl peroxide in an amount effective to ameliorate undesirable skin conditions. As used herein, an “effective amount” is an amount of a compound or composition having a benzoyl peroxide component of the present invention sufficient to induce a particular positive benefit to skin with skin symptoms. Say. The positive advantage is about health or it is more cosmetic in nature or it is a combination of the two. In certain embodiments, a positive advantage is achieved by contacting the skin with a combination of solvated benzoyl peroxide and / or one or more antibiotic components to improve skin symptoms such as Acne vulgaris.

  The particular concentration of benzoyl peroxide in the composition will generally depend on the purpose for which the composition is to be applied. For example. The dosage and frequency of application can vary depending on the type and extent of skin symptoms.

  The treatment according to the present invention brings the skin into contact with benzoyl peroxide in an amount effective to ameliorate the skin symptoms associated with acne. In some embodiments, a patient is treated by topically applying one or more benzoyl peroxide compositions to the skin with symptoms associated with acne. The active ingredient is applied until a therapeutic goal is achieved. However, the duration of treatment can vary depending on the degree of symptoms. For example, treatment ranges from weeks to months, depending on whether the goal of treatment is to reduce or eliminate skin symptoms associated with acne.

  Treatment according to the present invention increases the percutaneous absorption of benzoyl peroxide by contacting the skin with an effective amount of one or more benzoyl peroxide compositions according to the present invention. In some embodiments, the patient is treated with dissolved benzoyl peroxide by topically applying the dissolved mixture to the skin. Benzoyl peroxide is applied until an absorption goal is achieved. In some embodiments, percutaneous absorption of benzoyl peroxide is increased compared to application of an undissolved benzoyl peroxide composition. Thus, higher concentrations of benzoyl peroxide are found on the surface of the epidermis, stratum corneum and stratum corneum in a single application when compared to formulations utilizing undissolved benzoyl peroxide.

The following examples (but not limited to) further illustrate the compositions, methods and treatments according to the present invention. It should be noted that the present invention is not limited to the specific details embodied in the examples.
In the following Examples 1-6, a clear serum having the indicated composition was formulated.

Dimethylisosorbide 21.6%
Benzoic acid 2-phenylethanol ester 21.6%
Benzoyl peroxide, wet with 26% water 3.14%
Benzoic acid 5.0%
Salicylic acid 2.0%
Benzyl alcohol 21.66%
Propylene glycol monomethyl ether 25.0%

Dimethylisosorbide 21.6%
Benzoic acid 2-phenylethanol ester 21.6%
Benzoyl peroxide, wet with 26% water 3.14%
Benzoic acid 5.0%
Salicylic acid 2.0%
Benzyl alcohol 21.66%

Dimethylisosorbide 21.6%
Benzoic acid 2-phenylethanol ester 21.6%
Benzoyl peroxide, wet with 26% water 3.14%
Benzoic acid 5.0%
Salicylic acid 2.0%
Benzyl alcohol 21.66%
Ethanol 25.0%

Dimethyl isosorbide 25.0%
Benzoic acid 2-phenylethanol ester 24.0%
Benzoyl peroxide, wet with 26% water 3.14%
Benzoic acid 5.0%
Salicylic acid 2.0%
Benzyl alcohol 25.86%
Propylene glycol monomethyl ether 15.0%

Dimethyl isosorbide 25.0%
Benzoic acid 2-phenylethanol ester 26.0%
Benzoyl peroxide, wet with 26% water 3.14%
Benzoic acid 5.0%
Salicylic acid 2.0%
Benzyl alcohol 25.86%

Dimethyl isosorbide 25.0%
Benzoic acid 2-phenylethanol ester 24.0%
Benzoyl peroxide, wet with 26% water 3.14%
Benzoic acid 5.0%
Salicylic acid 2.0%
Benzyl alcohol 25.86%
Ethanol 15.0%

These compositions were made by adding benzoyl peroxide to a solvent to form a mixture at low temperature. Next, other ingredients were added while continuing mixing to obtain a transparent cosmetic product.
In Examples 7-18 below, clear cosmetic liquids were formulated having the following ingredients expressed in weight percent of the total composition.

Benzoyl peroxide 10
Benzylbenzoate 85
Acetone 5

Benzoyl peroxide 10
Acetone 5
Benzoic acid 2-phenylethyl ester 85

Benzoyl peroxide 10
Dimethylisosorbide 30
Benzyl benzoate 60

Benzoyl peroxide 10
Dimethyl isosorbide 40
Benzoic acid 2-phenylethyl ester 30
Benzyl alcohol 20

Benzoyl peroxide 8
Dimethylisosorbide 46
Benzoic acid 2-phenylethyl ester 46

Benzoyl peroxide 8
Dimethyl isosorbide 43.5
Benzoic acid 2-phenylethyl ester 43.5
Ethoxyethanol 5

Benzoyl peroxide 8
Dimethylisosorbide 45
Benzoic acid 2-phenylethyl ester 23.5
Benzyl alcohol 23.5

Benzoyl peroxide 8
Dimethylisosorbide 45
Benzoic acid 2-phenylethyl ester 18.5
Benzyl alcohol 18.5
Ethoxyethanol 10

Benzoyl peroxide 8
Dimethylisosorbide 45
Benzyl benzoate 18.5
Benzyl alcohol 18.5
Ethoxyethanol 10

Benzoyl peroxide 8
Dimethylisosorbide 45
Benzoic acid 2-phenylethyl ester 37
Ethoxyethanol 10

Benzoyl peroxide 8
Dimethylisosorbide 45
Benzoic acid 2-phenylethyl ester 34
Benzyl alcohol 3
Ethoxyethanol 10

Benzoyl peroxide 6.25
Dimethyl isosorbide 40
Benzyl benzoate 42.45
Vitamin A acetate 0.5
BHT 0.8
Ethoxydiglycol 10

  These compositions were made by adding benzoyl peroxide to a solvent to form a mixture at room temperature. Next, while continuing mixing, other ingredients were added to obtain a transparent serum.

A suitable composition can be formulated having the ingredients expressed as weight percent of the total composition.
Component amount Benzoyl peroxide 4.0-6.25
Benzoyl benzoate 35-50
Dimethylisosorbide 30-50
BHT 0.2-5
Ethoxydiglycol 5-20
Volatile silicone 0-20
Fumigated silica 0-10

An emulsion having the following composition was formulated:
Component amount of water 67.6
Steerless 40 0.8
Glycerin 4.0
Benzoyl peroxide 74% 7.0
Benzyl benzoate 10.0
Cyclomethicone 5.0
Ethylenediaminetetraacetic acid disodium salt (EDTA) 0.1
Stearyl alcohol 4.0
Steerless 2 1.5

This composition was prepared as follows.
(Phase A) Water, glycerin and EDTA were heated to 75 ° C. in a main vessel.
(Phase B) Steareth 40, cyclomethicone, steareth 2 and stearyl alcohol were heated to 75 ° C. in an auxiliary container.

Phase B was added to Phase A with mixing. Cooled down.
(Phase C) Benzoyl peroxide and benzyl benzoate were mixed at room temperature.
Phase C was added to the above mixture of Phase A and Phase B with cooling at a temperature below 40 ° C. The emulsion was cooled to room temperature.

Emulsion formulation.
Phase A component amount (%)
Water content of benzoyl peroxide 75% 8.68
Benzyl benzoate 10.00
BHT 0.4
Vitamin A acetate 0.5
Dimethyl isosorbide 3.00
Benzoyl peroxide was added to a container with benzyl benzoate, BHT and vitamin A acetate and stirred for 30 minutes. Dimethyl isosorbide was added and mixed for another 10 minutes.

Phase B component amount (%)
DI water 74.22
Phenoxyethanol 0.1
EDTA disodium salt 0.1
Hydroxyethyl acrylate / sodium acryloyldimethyl 3.0
Laurate copolymer + squalane + polysorbate 60
Phase B ingredients were mixed and dispersed. Under strong shear mixing, Phase A was added and mixed until a uniform emulsion (oil-in-water) was obtained. If other materials with the desired properties were stable with the organic peroxide, they were added.

Emulsion formulation.
Emulsion formulation.
Phase A component amount (%)
Water content of benzoyl peroxide 75% 8.68
Benzyl benzoate 10.50
BHT 0.4
Dimethyl isosorbide 3.00
To a vessel with benzyl benzoate and BHT, benzoyl peroxide was added and stirred for 30 minutes. Dimethyl isosorbide was added and mixed for another 10 minutes.

Phase B component amount (%)
DI water 74.22
Phenoxyethanol 0.1
EDTA disodium salt 0.1
Hydroxyethyl acrylate / sodium acryloyldimethyl 3.0
Laurate copolymer + squalane + polysorbate 60
Phase B ingredients were mixed and dispersed. Under strong shear mixing, Phase A was added and mixed until a uniform emulsion (oil-in-water) was obtained. If other materials with the desired properties were stable with the organic peroxide, they were added.

This example illustrates in vitro transdermal absorption of a topical benzoyl peroxide composition according to the present invention in the skin.
(Materials and methods)
Cumulative transdermal absorption of five formulations of C ¹⁴ radiolabeled benzoyl peroxide formulation was measured on human rod skin for 8 hours using a Franz in vitro diffusion chamber. More particularly, a 5% benzoyl peroxide formulation according to the present invention (meeting US Pharmacopoeia labeling requirements) is converted to a 10% benzoyl peroxide formulation, 10% benzoyl peroxide gel, 5% benzoyl peroxide. Comparison was made with four compositions comprising the formulation and a 6% benzoyl peroxide hydrogel formulation. The skin. Sourced from the same donor and contained no damaged tissue, holes, nevus, infectious disease and other irregularities. 15 g of benzoyl peroxide was applied to the skin (surface area 1.7 cm ² ) with a rubber spatula. At 8 hours, the percent of benzoyl peroxide recovered at the stratum corneum, epidermis and stratum corneum surfaces was determined by calculating the percent recovery of the total amount of benzoyl peroxide applied. The total mcg (micrograms) of benzoyl peroxide recovered from each location was calculated by multiplying the total mcg of the applied product by the% recovered.

(result)
After 8 hours of treatment, the total mcg of labeled benzoyl peroxide and the% of the applied dose recovered on the combined epidermis, stratum corneum and stratum corneum surface is in accordance with the present invention over all other formulations. The 5% benzoyl peroxide composition was large. Table 1 below shows the percent benzoyl peroxide and mcg recovered at the epidermis, stratum corneum and stratum corneum surface combined after 8 hours.

Table 1
Total application amount of composition (μg) Total recovery amount (μg) Total recovery%
5% benzoyl peroxide composition 800 309 38.6
10% benzoyl peroxide formulation 1502 181 12.0
10% benzoyl peroxide gel 1464 168 11.4
8% benzoyl peroxide formulation 1004 92 9.1
6% benzoyl peroxide hydrogel 658 68 10.3

  The% benzoyl peroxide recovered was always higher in the skin compartment with the 5% benzoyl peroxide composition according to the invention than with the other formulations. Table 2 below shows the percent of benzoyl peroxide recovered on the combined epidermis, stratum corneum and stratum corneum surface after 8 hours.

Table 2
Composition epidermal stratum corneum surface stratum corneum surface 5% benzoyl peroxide composition 3.6 14.7 14.6
10% benzoyl peroxide formulation 1.3 5.5 5.3
10% benzoyl peroxide gel 2.1 4.8 4.3
8% benzoyl peroxide formulation 1.3 4.0 2.3
6% benzoyl peroxide hydrogel 2.2 3.4 2.0

  The recovered mcg of recovered benzoyl peroxide was always greater in the skin compartment with the 5% benzoyl peroxide composition according to the present invention than the other formulations. Table 3 below shows the recovered mcg of benzoyl peroxide on the combined epidermis, stratum corneum and stratum corneum surface after 8 hours.

Table 3
Composition epidermal stratum corneum surface stratum corneum surface 5% benzoyl peroxide composition 33.9 137.6 137.2
10% benzoyl peroxide formulation 20.1 81.8 79.2
10% benzoyl peroxide gel 32.0 71.4 64.2
8% benzoyl peroxide formulation 16.9 47.9 28.1
6% benzoyl peroxide hydrogel 19.6 30.4 18.0

(Discussion)
The in vitro percutaneous absorption of the 5% benzoyl peroxide composition according to the present invention at the epidermis, stratum corneum and stratum corneum surface was greater than that observed for formulations with larger dispersed particles in other products. As transdermal absorption increases, the formulations according to the invention are believed to provide more effective bactericidal activity as well as longer sterilization times.

This example illustrates the antibacterial efficacy of a topical benzoyl peroxide composition according to the present invention under study for 3 days.
(Materials and methods)
A random examination of the divided faces of 24 subjects was performed. Subjects were randomly divided into two groups of 12 people each. Each subject was subjected to forehead and cheek mapping for treatment and sampling location. In general, the planned location on the eye was confirmed and used. Each side of the forehead was processed by a technician and a uniform 0.20 ml volume was applied. In one aspect, a commercial 5% benzoyl peroxide gel or a commercial combination of 5% benzoyl peroxide and 1% clindamycin gel is applied, while in the opposite aspect, a 5% benzoyl peroxide composition (US Meets pharmacopoeia labeling requirements). Subjects were forbidden to wash their face after 10 pm before the start of the test and in the morning of the test. Acne counts and subsequent counts were established.

Bacteriological sampling was performed using the technique of cyanoacrylate follicle biopsy. For follicular biopsy, a drop of cyanoacrylate glue was applied on a plastic slide to an area of approximately 1 × 1 cm. The slide was then pressed against the skin until polymerization occurred and gently peeled off. Under the microscope, the 20 largest follicular plugs were removed over the peeled surface and transferred to a carrier broth. All samples were then transferred onto Brucella agar supplemented with yeast extract, dextrose and cysteine. Plates were incubated anaerobically at 35-37 ° C for 7 days and counted P.P. acne units (cfu) were formed. For all samples, P.I. The density of acne was expressed as log ₁₀ cfu per cm ² .

  Baseline sampling had one cyanoacrylate follicle biopsy on the right and left forehead. Bacteriological sampling was repeated at 3 and 8 hours after application. Male subjects were instructed not to shave their faces during the test. Subjects were instructed not to wash their face until after the 24th reading on the next day, and then instructed to wash with water only until the study was completed. Subjects returned to 24, 48 and 72 hours for further sampling, and a total of 6 cyanoacrylate follicular biopsies were performed on each subject during the 3-day study.

(result)
A 5% benzoyl peroxide composition according to the present invention has a P.A. concentration greater than that of a 5% benzoyl peroxide gel after 3 and 8 hours based on data from a forehead follicular biopsy. acne decreased by 0.2 log (see, for example, FIG. 1) and 5% benzoyl peroxide, 1% clindamycin gel to give P. acne. The acne was reduced by 0.7 log (see, for example, FIG. 2).

(Conclusion)
The benzoyl peroxide composition according to the present invention has been shown to be an effective antibacterial agent against acne. The 5% benzoyl peroxide composition according to the present invention has a P.I. A large in vivo bactericidal activity was demonstrated against acne.

This example illustrates lesion reduction using a topical 5% benzoyl peroxide composition according to the present invention.
(Materials and methods)
Subjects will be randomly divided and applied to the face with a 5% benzoyl peroxide composition according to the present invention (meeting US Pharmacopoeia labeling requirements) or 5% benzoyl peroxide / 1% cup. Lindamycin gel mix was applied. A controlled amount of study product (0.50 mL) was applied to the face twice daily for 10 weeks. To ensure precise observation, a map was created to examine each subject's forehead and cheeks. For all samples, lesions were expressed as% non-inflammatory lesions and% inflammatory lesions.

(result)
Subject assessment revealed that all products achieved a reduction in acne lesions (see, eg, FIG. 3). The composition according to the present invention achieved a reduction in lesions similar to that of the combination product containing both benzoyl peroxide and antibiotics (see eg FIG. 4).

(Conclusion)
The benzoyl peroxide composition according to the present invention has been shown to be an effective treatment for treating acne lesions. The composition according to the invention has demonstrated a reduction in lesions similar to a product combining both antibacterial agents and benzoyl peroxide.

  It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting the present invention, but is merely exemplary of embodiments. Those skilled in the art will envision modifications within the scope and spirit of the claims appended hereto.

2 shows a comparison between a 5% benzoyl peroxide gel and the composition according to the present invention (OMP) for the antibacterial activity of follicles forehead for more than 8 hours after one application. 2 shows a comparison of a 5% benzoyl peroxide / 1% clindamycin gel with a composition according to the present invention (OMP) for antibacterial activity of follicles over 8 hours after a single application. Comparison of non-inflammatory lesion counts in the course of treatment between the composition according to the invention (5% benzoyl peroxide solution) (ON) and 5% benzoyl peroxide gel / 1% clindamycin sulfate composition (BN) Show. Figure 2 shows a comparison of inflammatory lesion counts in the course of treatment between a composition according to the invention (5% benzoyl peroxide solution) (OI) and a 5% benzoyl peroxide gel / 1% clindamycin sulfate composition (BI). .

Claims (21)

  A composition comprising a solution of benzoyl peroxide dissolved in one or more solvents.   2. The composition of claim 1 further comprising an additional active ingredient effective to treat acne.   One or more solvents are benzoic acid, benzyl alcohol, salicylic acid, short chain alkyl ester of phenol or phthalic acid; benzoic acid, benzyl alcohol, salicylic acid, short chain alkyl ether of phenol or phthalic acid; benzoic acid, benzyl alcohol Short chain alkyl aldehydes of salicylic acid, phenol or phthalic acid; short chain alkyl ketones of benzoic acid, benzyl alcohol, salicylic acid, phenol or phthalic acid; short chain alkyls of benzoic acid, benzyl alcohol, salicylic acid, phenol or phthalic acid Benzoic acid, benzyl alcohol, salicylic acid, aryl ester of phenol or phthalic acid; benzoic acid, benzyl alcohol, salicylic acid, aryl ether of phenol or phthalic acid; benzoic acid, Aryl aldehydes of benzyl alcohol, salicylic acid, phenol or phthalic acid; consisting of benzoic acid, benzyl alcohol, salicylic acid, aryl ketone of phenol or phthalic acid and benzoic acid, benzyl alcohol, salicylic acid, phenol or aryl alcohol of phthalic acid The composition of claim 1 selected from the group.   One or more solvents may be alkyl esters of benzoic acid, alkyl esters of benzyl alcohol, alkyl esters of salicylic acid, alkyl esters of phenol, alkyl esters of phthalic acid, alkyl ethers of benzyl alcohol, alkyl ethers of phthalic acid, benzyl alcohol The composition of claim 1 selected from the group consisting of alkyl ethers of the following and alkyl ethers of phenol.   One or more solvents are benzoyl benzoate, benzoyl alcohol, diethyl phthalate, 2-phenylethyl ester benzoate, methyl salicylate, ethyl salicylate, propyl salicylate, butyl salicylate, ethyl benzoate, methyl benzoate, Propyl benzoate, butyl benzoate, dimethyl phthalate, diethyl phthalate, benzyl ethyl ether, benzyl methyl ether, phenetol, phenyl acetone, phenyl ethyl alcohol, phenoxy ethanol, phenyl acetaldehyde, ethyl phenyl acetone, phenyl methyl ketone, phenyl acetate, acetic acid Benzyl, benzyl acetoacetate, benzyl formate, benzaldehyde, benzyl alcohol, ethyl benzyl alcohol, salicyl aldehyde, benzyl salicylate, Rutoriruketon, phenyl benzoate, phenyl ether, dibenzyl ether, benzyl benzoate, 2-phenylethyl benzoate ester and composition of Claim 1 which is selected from the group consisting of.   The composition of claim 1, further comprising an additional component, wherein the additional component comprises a thickener, a rheology modifier, a secondary solvent, and combinations thereof. Secondary solvent, ethanol, acetone, dimethyl isosorbide, and the composition of claim 6 which is selected from C ₁ -C ₆ alcohol glycol ethers, and combinations thereof with 2 moles of ethylene oxide.   Secondary solvent is glycol glycol ether of phenol using 2 mol or less of ethylene oxide, glycol ether of methanol using 2 mol or less of ethylene oxide, glycol ether of ethanol using 2 mol or less of ethylene oxide, 2 mol or less of ethylene oxide The composition of claim 6 selected from the group consisting of glycol ethers of propanol used and combinations thereof.   A transparent facial toner comprising the composition of claim 1.   A transparent facial serum containing the composition of claim 1.   A stick comprising the composition of claim 1.   A topical composition comprising the composition of claim 1.   A method for treating acne, comprising contacting a user's skin with a topical composition comprising the composition of claim 1.   A method for treating acne comprising topically applying an effective amount of the composition of claim 1 to a person in need of acne treatment.   A method of treating a skin lesion comprising topically applying an effective amount of the composition of claim 1 to a person in need of treatment of the skin lesion.   A benzoyl peroxide / solvent solution is prepared by combining benzoyl peroxide and at least one solvent, and the benzoyl peroxide / solvent solution is applied topically to the skin, in which case percutaneous absorption of benzoyl peroxide is achieved. A method for improving the transdermal absorption of a benzoyl peroxide composition applied topically to a user's skin, characterized in that it is increased compared to the application of an undissolved benzoyl peroxide composition.   Benzoyl peroxide and at least one solvent are combined to provide a benzoyl peroxide / solvent solution and formulate a product suitable for topical application to the skin containing the benzoyl peroxide / solvent solution. how to.   18. The method of claim 17, further comprising adding an aqueous phase to the peroxide solution to form an emulsion.   18. The method of claim 17, wherein the aqueous phase comprises at least one component selected from the group consisting of surfactants, wetting agents, suspending agents, buffer systems, and combinations thereof.   18. A method of treating acne comprising applying a product produced by the method of claim 17 to the skin of a patient with acne.   A method for increasing percutaneous absorption of benzoyl peroxide, characterized in that the product produced by the method of claim 17 is applied to the skin of a patient.

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